1. Field of the Invention
The present invention relates to medicaments for the therapeutic and prophylactic treatments of diseases caused by smooth muscle cell hyperplasia. More specifically, it relates to medicaments for the therapeutic and prophylactic treatments of diseases caused by smooth muscle cell hyperplasia which comprise as active ingredients specific aminopyridazine derivatives and salts thereof.
2. Related Art
Percutaneous transluminal coronary angioplasty (PTCA) and percutaneous transluminal angioplasty (PTA) have recently been widespread as methods for surgical treatments of constricted blood vessels. These methods comprise the steps of remotely inserting a balloon-catheter from femoral arteries or the like, and inflating the balloon at a constricted site to physically expand the vessel. However, restenosis are sometimes observed from 3 to 6 months after operations according to these treatments. In the restenosis, no deposition of cholesterol can be observed, while there is observed so-called cellular fibrous intimal hyperplasia predominantly consisting of smooth muscle cells and intercellular matrixes produced by these cells (Journal of American College of Cardiology, Vol. 23(6), pp.1278-1288, 1994, May). Furthermore, stenosis after the implantation of organs, e.g. heart, liver, kidney and vessels, is also caused by smooth muscle cell hyperplasia (FASEB Journal Vol. 7, pp.1055-1060, 1993, August).
Therefore, it is expected to be effective to inhibit migration and proliferation of smooth muscle cells generated in intravascular lumens for the therapeutic and prophylactic treatments of restenosis after the PTCA and PTA operations and stenosis after the implantation of organs.
In order to achieve the foregoing objects, researches on new drugs have been conducted [see, for example, Japanese Patent Unexamined Publication (KOKAI) Nos.(Sho)57-38715/1982, (Hei)2-121922/1990, (Hei)3-83923/1991, (Hei)3-83957/1991, (Hei)3-118383/1991, (Hei)4-99775/1992, and (Hei)4-154720/1992]. However, they have not been clinically developed so far.
It has been reported that various types of phthalazine derivatives have a wide variety of pharmacological activities. For example, as compounds having potent inhibitory activities in vivo on platelet aggregation, Japanese Patent Unexamined Publication (KOKAI) Nos.(Sho)56-53659/1981, (Sho)56-53660/1981, and (Sho)57-48972/1982 disclose 1-anilino-4-phenylphthalazine derivatives, and (Sho)60-218377/1985 and (Sho)60-243074/1985 disclose compounds represented by the following formulas. ##STR2##
As to 1-amino-4-phenylphthalazine derivatives disclosed in British Patent No. 1303061 and Journal of Medicinal Chemistry (J. Med. Chem.), 12, 555 (1969), their anti-inflammatory and antirheumatic activities are solely described in the references.
In addition, European Patent Publication No.449203 A1 (corresponding to JP KOKAI (Hei)4-211666/1992) discloses 1-.alpha.-substituted-benzylamino-4-phenylphthalazine derivatives, and European Patent Publication No.534443 A1 discloses 3,6-di-substituted-pyridazine derivatives. It is disclosed that both of them have potent inhibitory activities on platelet aggregation, and that they can be expected to have efficacy on cerebrovascular diseases such as cerebral thrombosis and brain embolism, ischemic heart diseases such as cardiac infarction, and circulatory disorders such as peripheral circulatory disturbance based on their activities.
However, it has not been known that these phthalazine compounds have inhibitory activities on smooth muscle cell hyperplasia.